Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells.

Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.

Ablation of lysophosphatidic acid receptor 1 attenuates hypertrophic cardiomyopathy in a mouse model.

Myocardial fibrosis is a key pathologic feature of hypertrophic cardiomyopathy (HCM). However, the fibrotic pathways activated by HCM-causing sarcomere protein gene mutations are poorly defined. Because lysophosphatidic acid is a mediator of fibrosis in multiple organs and diseases, we tested the role of the lysophosphatidic acid pathway in HCM. Lysphosphatidic acid receptor 1 (LPAR1), a cell surface receptor, is required for lysophosphatidic acid mediation of fibrosis. We bred HCM mice carrying a pathogenic myosin heavy-chain variant (403+/-) with Lpar1-ablated mice to create mice carrying both genetic changes (403+/- LPAR1 -/-) and assessed development of cardiac hypertrophy and fibrosis. Compared with 403+/- LPAR1WT, 403+/- LPAR1 -/- mice developed significantly less hypertrophy and fibrosis. Single-nucleus RNA sequencing of left ventricular tissue demonstrated that Lpar1 was predominantly expressed by lymphatic endothelial cells (LECs) and cardiac fibroblasts. Lpar1 ablation reduced the population of LECs, confirmed by immunofluorescence staining of the LEC markers Lyve1 and Ccl21a and, by in situ hybridization, for Reln and Ccl21a. Lpar1 ablation also altered the distribution of fibroblast cell states. FB1 and FB2 fibroblasts decreased while FB0 and FB3 fibroblasts increased. Our findings indicate that Lpar1 is expressed predominantly by LECs and fibroblasts in the heart and is required for development of hypertrophy and fibrosis in an HCM mouse model. LPAR1 antagonism, including agents in clinical trials for other fibrotic diseases, may be beneficial for HCM.

Evaluation of Factors Associated with, and Outcomes for Patients with Nonhome Discharge Destinations Following Carotid Endarterectomy.

INTRODUCTION: Following a carotid endarterectomy (CEA) procedure, patients are discharged to their homes or other locations than home such as an acute care facility or skilled nursing facility based on their functional status and level of medical attention needed. Decision-making for discharge destination following a CEA to home or nonhome locations is important due to the differences in survival and postoperative complications. While primary outcomes such as mortality and occurrence of stroke following CEA have been extensively studied, there is a paucity of information characterizing outcomes of discharge destination and the factors associated. The purpose of this study was to explore the factors associated with discharge to nonhome destinations after CEA, and outcomes after discharge. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database, we identified patients who underwent CEA from 2011 to 2018. Patients were divided into two groups based on their discharge destination (home versus nonhome). Univariate and multivariate analysis were performed for preoperative and intraoperative factors associated with different discharge destinations. Postoperative complications associated with discharge to nonhome destinations were analyzed and mortality after discharge from hospital was compared between the 2 groups. RESULTS: A total of 25,094 patients met the criteria for inclusion in the study, of which 39% were females and 61% were males; median age was 71 years. Twenty four thousand one hundred twenty-five patients (93.13%) were discharged to home (Group I) and 1,779 (6.87%) were discharged to nonhome destinations (Group II). Following preoperative and intraoperative factors were associated with discharge to nonhome locations: older age, diabetes mellitus, functional independent status, transfer from other hospitals, symptomatic status, need for preoperative blood transfusions, severe ipsilateral carotid stenosis, elective CEA, need for intraoperative shunt and general anesthesia (all P< 0.05). Following postoperative complications had statistically significant association with discharge to nonhome destinations: postoperative blood transfusion, pneumonia, unplanned intubation, longer than 48 hours on ventilator, development of stroke, myocardial infarction, deep vein thrombosis, and sepsis (all P< 0.05). Mortality after discharge from hospital was 0.39% (n = 100). Mortality among those who were discharged to home was 0.29% vs. 1.63% for those who were discharged to nonhome locations (P< 0.05). CONCLUSIONS: Majority of the patients after CEA are discharged back to their homes. This study identifies the factors which predispose patients discharged to locations, other than home. Patients who are not discharged home have higher mortality as compared to those who are discharged to their homes.